Two decades since the development of effective antiretroviral therapy (ART) for HIV infection, HIV-positive people who use illicit drugs (PWUD) continue to experience persistent disparities in HIV treatment outcomes. Although the deleterious impact of high-intensity illicit drug use on access and adherence to ART is clear, the social, structural and economic barriers to engagement and retention in HIV care remain incompletely described, and there is an urgent need to identify aspects of treatment for HIV and addiction that promote optimal HIV treatment outcomes. At the same time, there is an increasing appreciation of the importance of HIV-associated comorbidities, coinfections and complications?especially immunologic dysfunction, chronic inflammation and premature aging?on HIV disease outcomes, even among HIV-positive individuals optimally engaged in ART. Although the impact of some comorbidities, such as hepatitis C virus co-infection, on HIV-positive PWUD are well described, we are unaware of any longitudinal study using a validated measure incorporating HIV- and non- HIV-related clinical biomarkers to systematically investigate HIV disease severity, and the impact of illicit drug use and related social, structural and economic factors, among HIV-positive PWUD in a setting of no-cost universal medical care including all ART and medications for addiction treatment. Thus, in this application, we propose novel and significant investigations into the individual, social, structural and economic determinants of HIV treatment and disease outcomes among PWUD. Specifically, through the renewal of funding for a longstanding community-recruited prospective cohort of more than 1000 HIV-positive PWUD linked to comprehensive clinical monitoring data in Vancouver, Canada, we propose to: analyze the implementation, uptake and impact of new and emerging treatment for HIV and addiction on the achievement and maintenance of optimal HIV treatment and disease outcomes; investigate the impacts of established and emerging illicit drug use patterns and evolving approaches to addiction treatment on HIV treatment and disease outcomes; explore the interrelationships between social, structural and economic forces and illicit drug use patterns on HIV disease outcomes; and continue to serve as a NIDA-funded cohort that is a platform for a range of epidemiological, phylogenetic/bioinformatic and basic research into HIV acquisition, transmission and pathogenesis among people who use illicit drugs. This proposal to renew our research program exploits several established and emerging facets of the local environment, including: a centralized program of universal access to no-cost medical care, allowing for the complete ascertainment of clinical data free of the confounding influence of financial ability; the ongoing development of a range of innovative HIV and addiction programs for PWUD, including initiation of ART upon HIV diagnosis, harm-reduction-based HIV prevention and treatment supports; and novel approaches to manage opioid and stimulant use disorders. Our proposal is well aligned with recent calls for high-priority research to reduce disparities in HIV treatment and disease outcomes among HIV-positive PWUD through evidence to promote engagement and retention in HIV care and reduce the effect of comorbidities, complications and coinfections.